Rivastigmine and metabolite analogues with putative Alzheimer’s disease-modifying properties in a Caenorhabditis elegans model

Abstract

The development of polyphenols as drugs for Alzheimer's disease (AD) is thwarted by their meagre brain availability due to instability and poor druglikeness. Here we describe the successful development of stable, druglike polyphenolic analogues of the current AD drug rivastigmine, that have high apparent blood-brain barrier permeabilities and multifunctional properties for AD treatment. The compounds inhibit cholinesterases and amyloid beta (Aβ) fibrillation, protect against Aβ 42-induced toxicity in vitro, and demonstrate efficacy in vivo in a transgenic Caenorhabditis elegans model expressing Aβ 42 , with potencies similar to rivastigmine and natural polyphenols. The results suggest that a tertiary amine substituent is amenable for developing water-soluble, membrane-permeable polyphenols, and its incorporation adjacent to a hydroxy group is favourable for intramolecular hydrogen bonding that facilitates membrane permeability. Carbamylation of one hydroxy group protects the polyphenols from degradation and mostly improves their membrane permeability. These design strategies may assist in the development of polyphenol-based drugs.

SAR-mediated Similarity Assessment of the Property Profile for New, Silicon-Based AChE/BChE Inhibitors

“…The in vitro assessment of AChE/BChE and PET inhibitory profiles for the investigated pool of compounds was conducted and compared with marketed drugs; e.g., rivastigmine (RIV, Exelon®, Chicago, Illinois, USA), galanthamine (GLT,) and the commercially used herbicide 3-(3,4-dichlorophenyl)-1,1-dimethylurea (DCMU). Despite different mechanisms of action, RIV and GLT are the 2nd generation of ChEIs that pseudo-irreversibly inhibit AChE and BChE [51], respectively. DCMU is a sensitive and specific inhibitor of photosynthesis [52].…”

“…The crystallographic geometry of BChE with a catalytic core (CC) determined at a resolution of 2.6 Å in the liganded state (holo) with the RIV analog 3-[(1 R )-1-(dimethylamino)ethyl]-4-hydroxyphenyl ethyl(methyl)carbamate was downloaded from the Protein Data Bank repository (PDB entry code: 6EUL) [51,67]. The AutoDock Vina program was used to (re)dock the RIV analogue in the active site (AC2) of the enzymatic chain A that is comprised of six amino acids: Asn68, Ile69, Asp70, Trp82, Thr120 and Pro285, along with a 1,2-ethanediol molecule (EDO605).…”

Chiral Separation, X-ray Structure, and Biological Evaluation of a Potent and Reversible Dual Binding Site AChE Inhibitor

“…was soaked into trigonal crystals of TcAChE, obtained as described earlier, 18 and the structure of the The experimental electron density map revealed the presence of a water molecule (W1 in Figure 5) at 2.8 Å from the oxygen atom of the amide group of MC1420, and 2.7 Å from the nitrogen atom of the Phe288 backbone, distances both compatible with H-bond interactions. This water-mediated interaction, along with the two stacking interactions described above, comprise the whole set of significant protein-ligand interactions.…”

Structure-Based Scaffold Repurposing toward the Discovery of Novel Cholinesterase Inhibitors

“… 30 For example, aspirin, a well-known analgesic that has been in general use for over a century, was approved for the treatment of colorectal cancer in 2015. 31 Moreover, the availability of several hundred X-ray structures of AChE and BuChE co-crystallized with various ligands 22 , 32 , 33 provides further insights regarding essential features necessary for the development of novel ChEs inhibitors. Figure 2 provides an overview of the significant structural differences between the active sites of AChE and BuChE.…”